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Pharmaceutical companies Affymax and Takeda have announced a recall of all lots of their Omontys drug after becoming aware of more than a dozen cases of anaphylaxis, of which three were fatal to patients. The concerns are both serious and new, but a review of the drug's December 2011 advisory committee meeting transcript shows that they might not be entirely unexpected.

Prophetic Advisory Committee Hearing?

Omontys (peginestaide) Injection is an injectable drug indicated for the treatment of anemia due to chronic kidney disease, and was approved in March 2012 by US regulators. At the time, the US Food and Drug Administration (FDA) wrote that the drug was a step forward in that it allowed patients to be treated once per month instead of more frequently.

The drug experienced a relatively straightforward advisory committee hearing in December 2011 before the Oncologic Drugs Advisory Committee, with 15 members voting in favor of the drug, one voting against and one abstaining.

But at least one advisory committee member, Dr. Steven Nissen, raised a number of questions during the product's hearing in regards to the statistical methods used to validate the drug's safety and efficacy-questions that may now seem prophetic in the context of the current recall.

Nissen said during the hearing that he was particular concerned that the trial had cherry-picked too many ideal patients, and that the drug was in need of a "large, careful, randomized trial that includes all comers-it doesn't just take that low-risk subset that was studies in these trials and pulls them out, it gets everybody-and see whether or not the safety actually holds up in a proper, blinded, randomized control trials done in the best possible fashion."

"So what I'm fearful will happen is that those patients that fall outside of that narrow range that were in the dialysis study are actually going to get treated with the drug once it gets out there, and that you're going to be back here in front of this committee in the future, as you have been in the past, with this drug, as you have with other drugs, with some surprises down the road.&nbsp; And I would rather know that before a drug is approved then after a drug is approved," added Nissen.

Nissen's remarks may not have won over many others on the committee, 15 of whom voted to approve the drug, but they did garner the sympathies of Dr. Michael Flessner, director of inflammatory renal diseases at the National institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH).

"I voted yes because if you look at their intent to treat, design and count all four trials, they still made it on safety," explained Flessner. "However, I was and am, and probably will be for several years, deeply hoping that Dr. Nissen, whose opinion I respect very well, is right in his hope that we didn't miss a safety signal that we'll be sorry about, because however more convenient -- and I agree with all the things our patient said -- if we cause them more strokes, or more arrhythmias, or more deaths, then we will not have done them a good job." (Transcript, Page 242)

All Lots Recalled, FDA Advises Against Further Prescriptions

To be fair, the risks brought up at the advisory committee hearing were not related to anaphylaxis or other allergies, which do not once appear in the meeting transcripts. Page 21 of FDA's briefing report notes that "hypersensitivity or anaphylactic-type reactions were not reported."

But Nissen's concerns about trial size and enrollment may seem particularly prescient now that those risks have in fact been found and acknowledged as serious.

In a statement, Takeda said that at least 19 patients, or 0.2% of all patients, had experienced anaphylactic reactions to Omantys, of which three were fatal.

"The companies are actively investigating these cases," Takeda and Affymax wrote in a statement. "In the meantime, dialysis organizations are instructed to discontinue use. Customers will be provided instructions on how to return the product to the manufacturer for a refund."

The recall, announced on 23 February 2013, was also relatively unusual in that it prompted a press announcement from the US Food and Drug Administration (FDA), and on a Sunday-both far from commonplace.

"Due to the severity of the public health risk, we want to be certain that health care providers stop using Omontys," said Howard Sklamberg, director, Office of Compliance, FDA's Center for Drug Evaluation and Research (CDER). "Americans deserve medications that are safe, effective, and of the highest quality. We are investigating the products and facilities associated with this recall and will provide updates as we learn more."